Abstract Resistant hypertension (RHTN) is an emerging etiology and was defined as persistent elevation of blood pressure above goal despite concurrent use of 3 antihypertensive agents, each of unique class with a diuretic included among the treatment regimen, and with all drugs at target dose. It has been estimated that 12.8% of the hypertensive population in the U.S. met the strict definition for RHTN, and 10% of these patients are refractory to treatment even with 5-6 different classes of antihypertensives. RHTN patients have significantly increased risk of all-cause mortality, cardiovascular mortality, nonfatal stroke, and nonfatal myocardial infarction. While the antihypertensive treatment options have increased from just three classes in 1970' to over eleven different classes now, physicians are having difficulties to achieve controlled blood pressure in RHTN patients. In fact, there is scant evidence for beneficial outcomes using additional drug treatment after three antihypertensives have failed to achieve target blood pressure. Because reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischemic heart diseases by 21%, and reduce the likelihood of dementia and heart failure, clearly there is a substantial unmet medical need of novel therapeutics that can actively improve hemodynamics and endothelial function in RHTN patients. Importantly, an endocrine hormone?adrenomedullin (ADM)?was shown to be among the most potent hypotensive hormones and regulators of vascular barrier functions. ADM also exhibits neuroprotective, renoprotective, and diuresis effects in a variety of cardiovascular disease models. Despite its promise for treating a variety of cardiovascular diseases, wild-type ADM has short half-life. To overcome this obstacle, we have developed a group of super- agonistic ADM peptidomimetics that exhibit 10- to 100-fold higher potency on receptor activation. By serendipity, we have also discovered that select super-agonists self-assemble and form in situ gel depots. Together, these data suggested that the ADM analogs, which possess unrivaled super-agonistic activity and the novel self-assemble depot-formation capability, could be an ideal drug for sustained activation of ADM signaling in RHTN patients. Accordingly, we propose to investigate the translational potential of the super- agonist gels in an RHTN rat model. Successful development of the nanomedicine has the potential to drastically improve the care of patients with RHTN or other endothelial dysfunction-associated diseases.